Gut microbiota and treatment of cancer

Abstract

The ubiquitin ligase, RNF5, regulates the gut microbiota composition and influences the immune checkpoint response to tumors. RNF5 deficient animals exhibit significant inhibition of tumor development as well as an altered gut microbiota composition. Methods of treating cancer by administering to a subject one or more selected bacterial species and/or one or more prebiotics that promote the growth of one or more selected bacterial species are disclosed. Also disclosed are methods of treating cancer by administering to a subject one or more selected bacterial species and/or one or more prebiotics that promote the growth of one or more selected bacterial species in combination with one or more anti-cancer agents.

What is claimed is: 
     
       1. A method of treating colon cancer or melanoma in a human subject in need thereof, the method comprising administering to the human subject:
 a therapeutically effective amount of one or more bacteria selected from the group consisting of Acetatifactor  muris, Alistipes finegoldii, Lactobacillus animalis, Bacteroides sartorii , Muribaculum  intestinale, Parasutterella excrementihominis, Clostridium methylpentosum , and  Bacteroides rodentium , wherein the human subject is identified as having a mutation in Neuroblastoma RAS (NRAS) gene prior to treatment; and 
 administering one or more anti-cancer agents, wherein the one or more anti-cancer agents comprises a Serine/threonine-protein kinase B-raf (BRAF) inhibitor or a Mitogen-activated protein kinase kinase (MEK) inhibitor. 
 
     
     
       2. The method of  claim 1 , further comprising evaluating the gut microbiome of the human subject prior to the initiation of treatment. 
     
     
       3. A method of treating melanoma in a human subject having a gut microbiome, the method comprising:
 i) evaluating the gut microbiome of the human subject prior to the initiation of treatment, wherein the human subject is identified as having a mutation in the Neuroblastoma RAS (NRAS) gene prior to treatment; and 
 ii) administering to the human subject a composition comprising a therapeutically effective amount of one or more bacteria selected from the group consisting of  Oscillibacter valericigenes , Acetatifactor  muris, Alistipes putredinis , Alishpes  finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii , Muribaculum  intestinale, Parasutterella excrementihominis, Clostridium methylpentosum , and  Bacteroides rodentium ; and one or more anti-cancer agents, wherein the human subject is identified as having poor responsiveness to treatment with the one or more anti-cancer agents prior to initiating administration of the composition, wherein the one or more anti-cancer agents comprises a Serine/threonine-protein kinase B-raf (BRAF) inhibitor or the one or more anti-cancer agents comprises a Mitogen-activated protein kinase kinase (MEK) inhibitor. 
 
     
     
       4. The method of  claim 3 , wherein the one or more anti-cancer agents comprises an immune checkpoint regulator. 
     
     
       5. The method of  claim 4 , wherein the immune checkpoint regulator is a checkpoint activator. 
     
     
       6. The method of  claim 4 , wherein the immune checkpoint regulator is a checkpoint inhibitor. 
     
     
       7. The method of  claim 3 , wherein the one or more anti-cancer agents comprises a Serine/threonine-protein kinase B-raf (BRAF) inhibitor. 
     
     
       8. The method of  claim 3 , wherein the one or more anti-cancer agents comprises a Mitogen-activated protein kinase kinase (MEK) inhibitor. 
     
     
       9. The method of  claim 3 , wherein the one or more anti-cancer agents comprises a BRAF inhibitor and a MEK inhibitor. 
     
     
       10. The method of  claim 7 , wherein the human subject is identified as having a mutation in the BRAF gene prior to treatment. 
     
     
       11. The method of  claim 10 , where wherein the human subject is identified as having the V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and/or A727V mutation in BRAF prior to treatment. 
     
     
       12. The method of  claim 3 , wherein the composition is administered orally. 
     
     
       13. The method of  claim 3 , wherein the one or more bacteria is selected from the group consisting of  Oscillibacter valericigenes , Acetatifactor  muris, Alistipes finegoldii, Lactobacillus animalis, Bacteroides sartorii , Muribaculum  intestinale, Parasutterella excrementihominis, Clostridium methylpentosum , and  Bacteroides rodentium.    
     
     
       14. The method of  claim 13 , further comprising administering to the human subject a therapeutically effective amount of mucin. 
     
     
       15. A method of treating colon cancer or melanoma in a human subject having a gut microbiome, comprising:
 i) evaluating the gut microbiome of the human subject prior to the initiation of treatment; and 
 ii) administering to the human subject a therapeutically effective amount of one or more bacteria selected from the group consisting of Acetatifactor  muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii , Muribaculum  intestinale, Parasutterella excrementihominis, Clostridium methylpentosum , and  Bacteroides rodentium ; and 
 an immune checkpoint activator, wherein the human subject is identified as having a mutation in the BRAF gene or the Neuroblastoma RAS (NRAS) gene prior to treatment. 
 
     
     
       16. The method of  claim 15 , wherein the immune checkpoint activator is an agonist antibody that binds to CD27, CD40, OX40, GITR, CD137, CD28, or ICOS. 
     
     
       17. The method of  claim 15 , wherein the human subject is identified as having a mutation in the Neuroblastoma RAS (NRAS) gene prior to treatment.